Project Summary ? Overall The TB Structural Genomics Consortium (TBSGC) is a collaborative research group that has studied TB?s causative organism, Mycobacterium tuberculosis (Mtb), for the past 15 years. Over the years we have focused our goals to concentrate on proteins that are drug targets for novel antibiotics, and proteins whose structure might contribute to our knowledge of vulnerabilities in Mtb. We also supplemented our structural work with both chemistry and genetics to validate our targets, to obtain and optimize protein inhibitors, and to determine their underlying biological roles within Mtb. Our multidisciplinary approach has allowed us to add considerable knowledge to mycobacterial structures, and to leverage this information to inform drug development. Significantly, results of the last TBSGC cycle has led to a novel anti-TB drug that is in late pre- clinical development along with others compounds that have been adopted by anti-TB drug developers. In this TBSGC renewal, we propose to incorporate new innovative technologies, including membrane protein structures and cryo-EM, to strengthen our commitment to TB drug development. We will leverage structure determination to both understand function and identify potential small molecule inhibitors. The fundamental goal of this project is to accelerate TB drug discovery by understanding essential functions of the mycobacterial cell and providing validated targets and inhibitors to our partners in the TB drug development community.